We propose to study mechanisms of immunoregulation within the premise that homeostasis of the immune system is highly complex and exists in multiple forms reflecting the multidimensional network created by the soluble and cellular components of adaptive immunity. Four specific sets of experimental approaches will be undertaken aimed at defining mechanisms of immunoregulation within the context of such immunological parameters as lymphocyte activation, lymphocyte differentiation and lymphocyte heterogeneity. These aims are: 1. To understand the mechanisms of the state of immunological unresponsiveness induced to human gamma globulin in T and B lympocytes of adult mice. Two sets of theoretical considerations will be tested, namely clonal deletion or active suppression. In part, this phase will test the hypothesis that interaction between the proper concentrations of antigen and either specific T or B cells will lead to direct inactivation of such cells unless there is interference of this process mediated by either macrophages for T cells) or T lymphocytes (for B cells). 2. To understand the mechanisms of immunological unresponsiveness induced in various stages of B and T cell differentiation. The hypothesis to be tested is whether there are stages of lymphocyte development in which interaction of specific cells and antigen can only lead to inactivation. 3. To understand the mechanisms by which unresponsiveness can be achieved by specific antibody. The hypothesis to be tested is whether blockage of the Fc receptor on lymphocytes and macrophages interferes with the process of lymphocyte activation. 4. To establish an in vitro system of antigen inducible primary response in human lymphoid cells for use in study of immunoregulation for potenital clinical applicability.